The instant invention relates to a novel process for the synthesis of amphetamine, methamphetamine, and related compounds from derivatives of phenylpropanolamine acid addition salts. This new process, applied to produce d-amphetamine, has several advantages over prior art d-amphetamine production routes: shorter cycle times, less labor-intensive steps, and better chemical hygiene. Certain combinations of pharmaceutically acceptable salts of d,l-amphetamine and d-amphetamine are useful in the treatment of attention deficit disorders.
Many methods of making amphetamine and related compounds are known in the prior art, including the commercially used Leukart-Wallach reaction for producing racemic amphetamine from phenylacetone. For example, in one commercial process, phenylacetone is reacted with formamide and formic acid to form (xc2x1)-N-formylamphetamine (racemic N-formylamphetamine). The racemic N-formylamphetamine is then hydrolyzed with sulfuric acid, the solution basified, and the resulting d,l-amphetamine ((xc2x1)-amphetamine; racemic amphetamine) is distilled with an overall yield of about 60%.
In the illegal syntheses of amphetamine and related compounds, such as those found on internet searches, phenylpropanolamine and pseudoephedrine, isolated from over-the-counter cough and cold products, are converted to amphetamine and methamphetamine respectively (see, for example, Otto Snow, Amphetamine Synthesis (Thoth Press: Spring Hill, Fla., 1998); http://www.hyperreal.org/drugs/synthesis/meth.synth.; or http://hive.lycaeum.org/book-store.htm/). Following one of the procedures used in illegal manufacture of amphetamine and related compounds, d,l-norephedrine was refluxed with hydriodic acid and red phosphorus to obtain a mixture of amphetamine and a compound believed to be a bis compound, 1-phenyl-2-(phenylisopropyl)aminopropane, in equal parts. By another procedure, heating norephedrine with thionyl chloride at reflux temperature, followed by catalytic hydrogenation of the resulting 2-amino-1-chloro-1-phenylpropane hydrochloride, gave amphetamine. To avoid the hazards of working with thionyl chloride, hydriodic acid, and red phosphorus, another route was desirable. The conversion of the hydroxyl group of phenylpropanolamine to a benzylic acyloxyester followed by removal by hydrogenolysis, the process of the instant invention, was investigated and found to be a good route. These three discrete synthetic routes are summarized in the examples of Scheme 1, with a process of the invention illustrated as the bottom pathway. In this Scheme, amphetamine is used for illustration only, these synthetic routes are applicable to related compounds with substitution patterns obvious to those skilled in the art. 
Currently, dextroamphetamine is obtained from racemic amphetamine through a lengthy, labor-intensive process. It is obtained in 23% yield from racemic amphetamine via tartrate salt resolution followed by basification and distillation. In the tartrate salt resolution step, a hot solution of 37% hydrochloric acid, methanol, tartaric acid, and the racemic amphetamine is drained from a reactor into stainless steel pots, and the hot mixture is allowed to cool undisturbed for 16 hours while the d-amphetamine tartrate salt predominantly crystallizes. The solvent is then decanted from each of the stainless steel pots and the recovered d-amphetamine tartrate salt is transferred by hand to a centrifuge, where the salt is spun dry, reslurried with methanol, and centrifuged dry again. The tartrate resolution step is then repeated until the salt obtained meets the melting point and optical rotation specifications desired.
Using the process of the invention, dextroamphetamine (S-(+)-amphetamine) can be stereospecifically prepared from a phenylpropanolamine having the S configuration at the carbon bearing the amino group, e.g., 1R,2S-(xe2x88x92)-norephedrine or 1S,2S-(+)-norpseudoephedrine (the erythro form of phenylpropanolamine is norephedrine and the threo form is norpseudoephedrine). In the process of the invention, the otherwise higher cost of the appropriate phenylpropanolamine diastereomers useful for preparing dextroamphetamine is offset by the shorter cycle times, a less labor-intensive process, and better chemical hygiene.
The process comprises ester formation and then removal of the benzylic acyloxy group by catalytic hydrogenation or catalytic transfer hydrogenation. As pointed out above, when it is applied to the production of d-amphetamine, the process has several advantages over current d-amphetamine production routes: shorter cycle times, less labor-intensive steps, and better chemical hygiene. Further optimization of yields and operation cycle times using optimization methods known to those skilled in the art would only increase these advantages.
The general process is shown in Scheme 2 below. 
In Scheme 2, R1 is hydrogen or a lower alkyl group;
each R2 is independently a hydrogen, halogen, lower alkyl group, lower alkoxy group, lower alkyl group substituted with 1 to 5 halogens, lower alkoxy group substituted with 1-5 halogens, or both R2 together when on adjacent carbons constitute a xe2x80x94O(CH2)xOxe2x80x94 group where x is 1 to 4, thereby forming a ring structure fused with the phenyl group;
R3 is a C1-C8-alkyl group, a C1-C12-aralkyl group, C1-C12-alkaryl group, or a phenyl group, each optionally substituted by 1 to 5 substituents selected from halogen, hydroxy, or C1-C6-alkyl; and
HX is an equivalent of an organic or inorganic acid, preferred acids include hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid and other carboxylic acids such as benzoic acid, tartaric acid, succinic acid, aspartic acid, saccharic acid, oxalic acid, malic acid, and the like.
In step A, the phenylpropanolamine salt starting material of formula II is acylated with an acylating agent, in this example, (R3CO)2O in R3CO2H, to form the corresponding acylated phenylpropanolamine salt of formula III in a solvent at elevated temperature. In step B, the acylated phenylpropanolamine salt of formula III is hydrogenated using catalytic hydrogenation or catalytic transfer hydrogenation to obtain a compound of formula I.
For a direct route to dextroamphetamine, both b 1R,2S-(xe2x88x92)-norephedrine and 1S,2S-(+)-norpseudoephedrine have the correct steric configuration at the carbon bearing the amino group necessary to produce d-amphetamine [S-(+)-amphetamine] as shown in Scheme 3. 1R,2S-(xe2x88x92)-norephedrine is generally commercially available. This same process produces d-methamphetamine starting with either 1R,2S-(xe2x88x92)-ephedrine or 1S,2S-(+)-pseudoephedrine. 
Definition of Terms and Conventions Used
Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification and appended claims, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.
In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C1-C10 alkyl means an alkyl group or radical having 1 to 10 carbon atoms. The term xe2x80x9clowerxe2x80x9d applied to any carbon-containing group means a group containing from 1 to 8 carbon atoms, as appropriate to the group (i.e., a cyclic group must have at least 3 atoms to constitute a ring). In general, for groups comprising two or more subgroups, the last named group is the radical attachment point, for example, xe2x80x9calkylarylxe2x80x9d means a monovalent radical of the formula Alkxe2x80x94Arxe2x80x94, while xe2x80x9carylalkylxe2x80x9d means a monovalent radical of the formula Arxe2x80x94Alkxe2x80x94 (where Alk is an alkyl group and Ar is an aryl group). Furthermore, the use of a term designating a monovalent radical where a divalent radical is suitable shall be construed to designate the divalent radical and vice versa. Unless otherwise specified, conventional definitions of terms control and conventional stable atom valences are presumed and achieved in all formulas and groups.
The terms xe2x80x9calkylxe2x80x9d or xe2x80x9calkyl groupxe2x80x9d mean a branched or straight-chain saturated aliphatic hydrocarbon monovalent radical having 1-10 carbons. This term is exemplified by groups such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), and the like. It may be abbreviated xe2x80x9cAlkxe2x80x9d.
The terms xe2x80x9calkenylxe2x80x9d or xe2x80x9calkenyl groupxe2x80x9d mean a branched or straight-chain aliphatic hydrocarbon monovalent radical of 2-10 carbons containing at least one carbon-carbon double bond. This term is exemplified by groups such as ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl, decenyl, and the like.
The terms xe2x80x9calkynylxe2x80x9d or xe2x80x9calkynyl groupxe2x80x9d mean a branched and straight-chain aliphatic hydrocarbon monovalent radical of 2-10 carbons containing at least one carbon-carbon triple bond. This term is exemplified by groups such as ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl, decynyl, and the like.
The terms xe2x80x9calkoxyxe2x80x9d or xe2x80x9calkoxy groupxe2x80x9d mean a monovalent radical of the formula AlkOxe2x80x94 where Alk is an alkyl group. This term is exemplified by groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, and the like.
The terms xe2x80x9caryloxyxe2x80x9d or xe2x80x9caryloxy groupxe2x80x9d mean a monovalent radical of the formula ArOxe2x80x94, where Ar is aryl. This term is exemplified by groups such as phenoxy, naphthoxy, and the like.
The terms xe2x80x9calkylcarbonylxe2x80x9d, xe2x80x9calkylcarbonyl groupxe2x80x9d, xe2x80x9calkanoylxe2x80x9d, or xe2x80x9calkanoyl groupxe2x80x9d mean a monovalent radical of the formula xe2x80x94C(O)Alk, where Alk is alkyl or hydrogen.
The terms xe2x80x9carylxe2x80x9d or xe2x80x9caryl groupxe2x80x9d mean a substituted or unsubstituted aromatic carbocyclic monovalent or divalent radical of from 6 to 14 carbon atoms having a single ring (e.g., phenyl or phenylene) or multiple condensed rings (e.g., naphthyl or anthryl). Unless otherwise specified, the aryl ring may be attached at any suitable carbon atom which results in a stable structure and, if substituted, may be substituted at any suitable carbon atom with one or more substituents selected from halogen, alkyl, alkoxy, aryl, acyl, nitro, cyano, and the like which results in a stable structure. Exemplary aryl groups include phenyl, naphthyl, anthryl, phenanthryl, indenyl, heptalenyl, biphenyl, biphenylenyl, azulenyl, pentalenyl, and the like. It may be abbreviated xe2x80x9cArxe2x80x9d.
The terms xe2x80x9carylcarbonylxe2x80x9d, xe2x80x9carylcarbonyl groupxe2x80x9d, xe2x80x9caroylxe2x80x9d or xe2x80x9caroyl groupxe2x80x9d mean a monovalent radical of the formula xe2x80x94C(O)Ar, where Ar is aryl as defined above.
The terms xe2x80x9cacylxe2x80x9d or xe2x80x9cacyl groupxe2x80x9d mean a monovalent radical of the formula xe2x80x94C(O)R, where R is a substituent selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, and the like, each may be optionally substituted with one or more groups selected from halogens, alkoxy, hydroxy, nitro, cyano, alkyl aryl, and the like. Preferably R is a lower alkyl or phenyl, each optionally substituted. As such, the terms comprise alkylcarbonyl groups and arylcarbonyl groups.
The term xe2x80x9cacylating agentxe2x80x9d means a reactant that, when reacted with a compound having a nucleophilic site capable of reaction with the acylating agent, causes an acyl group to be covalently bound to one or more sites on the compound. Acylating agents include, but are not limited to, reagents having the formula RC(O)X, in which X is a halogen, an acyloxy group of formula Rxe2x80x2C(O)Oxe2x80x94, where Rxe2x80x2 has the same meaning of the R group defined in the previous paragraph. As such, the term encompasses carboxylic acids, carboxylic acid anhydrides, lower esters of carboxylic acids, and acid halides. Preferably, the acylating agents are acid halides or acid anhydrides. Such acylating agents may be mono-, di-, tricarboxylic, or polycarboxylic acylating agents. The acid anhydrides may be symmetrical, asymmetrical, or mixed anhydrides. In addition, acylating agents include in situ-generated o-acyl isoureas, compounds produced from the reaction of an acid (e.g., bromoacetic acid) and a carbodiimide (e.g., DIC and DCC), and isolated o-acyl isoureas. Exemplary and preferred acylating agents include acetyl chloride, acetyl bromide, propionyl chloride, benzoyl chloride, acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, hexanoic anhydride, formic acetic anhydride, benzoic anhydride, trifluoroacetylchloride, methyl trifluoroacetate, ethyl trifluoroacetate, and the like.
The term xe2x80x9cacetylating agentxe2x80x9d means an acylating agent wherein the acyl group is acetyl.
The terms xe2x80x9cacylationxe2x80x9d, xe2x80x9cacylatingxe2x80x9d, and the like refer to a chemical reaction whereby an acyl group is added to another compound or moiety using an acylating agent.
The terms xe2x80x9cacetylationxe2x80x9d, xe2x80x9cacetylatingxe2x80x9d, and the like refer to a chemical reaction whereby an acetyl group is added to another compound or moiety using an acetylating agent.
The term xe2x80x9caliphatic groupxe2x80x9d means a non-aromatic straight or branched chain hydrocarbon group. As such, the term comprises alkyl, alkenyl, and alkynyl groups.
The term xe2x80x9calicyclic groupxe2x80x9d means a non-aromatic cyclic hydrocarbon group. As such, the term comprises cycloalkyl, cycloalkenyl, and cycloalkynyl groups.
The term xe2x80x9ccarboxylic acidxe2x80x9d means an organic acid of the formula RC(O)OH, where R is a substituent selected from hydrogen or a substituent selected from a lower aliphatic group, lower alicyclic group, an aryl group, an aryl-alkyl group, or an alkyl-aryl group optionally substituted by halogen, alkyl, alkoxy, aryl, etc. This term is exemplified by formic acid, acetic acid, propanoic acid, butanoic acid, 2-methylpropanoic acid, pentanoic acid, propenoic acid, 2-methylpropenoic acid, 2-butenoic acid, cinnamic acid, benzoic acid, cyclobutanecarboxylic acid, salicylic acid, and the like.
The term xe2x80x9cdicarboxylic acidxe2x80x9d means an organic acid of the formula R(C(O)OH)2, where R is either a bond (i.e., oxalic acid) or a divalent hydrocarbon group selected from a C1-C6 alkylene group optionally substituted with hydroxy, halogen, alkoxy, and the like, lower alicyclic group, an aryl group, an aryl-alkyl group, or an alkyl-aryl group. This term is exemplified by oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumeric acid, phthalic acid, isophthalic acid, terephthalic acid, saccharic acid and the like.
The term xe2x80x9ctricarboxylic acidxe2x80x9d means an organic acid of the formula R(C(O)OH)3, where R is either a bond (i.e., oxalic acid) or a substituent selected from a lower aliphatic group, lower alicyclic group, an aryl group, an aryl-alkyl group, or an alkyl-aryl group optionally substituted with hydroxy, halogen, alkoxy, and the like. This term is exemplified by citric acid.
The terms xe2x80x9calkylcarbonyloxyxe2x80x9d or xe2x80x9calkylcarbonyloxy groupxe2x80x9d mean a monovalent radical of the formula xe2x80x94OC(O)Alk, where Alk is alkyl optionally substituted with hydroxy, halogen, alkoxy, and the like.
The terms xe2x80x9carylcarbonyloxyxe2x80x9d or xe2x80x9carylcarbonyloxy groupxe2x80x9d mean a monovalent radical of the formula xe2x80x94OC(O)Ar, where Ar is aryl optionally substituted with hydroxy, halogen, alkoxy, and the like.
The term xe2x80x9cprecious metal catalystxe2x80x9d means a solid metal catalyst in whatever form suitable and effective for achieving the hydrogenation reactions of the instant invention. Exemplary and preferred precious metal catalysts include platinum, palladium, ruthenium, osmium, iridium, rhodium, and the like, or mixtures thereof, the metal or alloy provided in the form of: (a) a finely divided (e.g., powder, granules, etc.) or high surface area (e.g., porous, sponge, gauze platinum or palladium black) metal or alloy, (b) a precursor compound (e.g., the oxide) converted into the active catalyst before or during hydrogenation, or (c) distributed on an inorganic support, generally of high surface area, such as carbon, activated carbon, silica, alumina, or other metal oxides (e.g., calcium oxide), metal carbonates (e.g., calcium carbonate), metal sulfates (e.g., barium sulfate), or the like, wherein the supported precious metal is preferably present at 0.5 wt. % to 10 wt. %, more preferably 1 wt. % to 5 wt. %.